一线替雷利珠单抗联合化疗治疗程序性死亡配体1表达≥1%的晚期胃癌：RATIONALE-305回顾性分析
First-Line Tislelizumab Plus Chemotherapy for Advanced Gastric Cancer with Programmed Death-Ligand 1 Expression ≥ 1%: A Retrospective Analysis of RATIONALE-305.
作者信息
Moehler Markus, Oh Do-Youn, Kato Ken, Arkenau Tobias, Tabernero Josep, Lee Keun-Wook, Rha Sun Young, Hirano Hidekazu, Spigel David, Yamaguchi Kensei, Wyrwicz Lucjan, Disel Umut, Pazo-Cid Roberto A, Fornaro Lorenzo, Xu Yaling, Sheng Tao, Yang Silu, Kadva Alysha, Cruz-Correa Marcia, Xu Rui-Hua
机构信息
Department of Medicine, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
Department of Hemato-Oncology, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
出版信息
Adv Ther. 2025 May;42(5):2248-2268. doi: 10.1007/s12325-025-03133-7. Epub 2025 Mar 13.
INTRODUCTION
Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score < 1 or TAP score < 1%, due to an unfavorable benefit-risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score ≥ 1%.
METHODS
Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score ≥ 1%.
RESULTS
At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score ≥ 1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0 months (95% confidence interval [CI] 13.3-16.7) vs. 12.8 months (95% CI 12.1-14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67-0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals.
CONCLUSIONS
Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score ≥ 1%.
TRIAL REGISTRATION NUMBER
NCT03777657.
简介
在RATIONALE-305研究中，对于局部晚期不可切除或转移性人表皮生长因子受体2（HER2）阴性胃癌/胃食管交界癌（GC/GEJC）患者，在意向性治疗人群以及程序性死亡配体1（PD-L1）肿瘤区域阳性（TAP）评分≥5%的患者中，替雷利珠单抗联合研究者选择的化疗（ICC）与安慰剂联合ICC相比，总生存期（OS）有统计学意义的改善。美国食品药品监督管理局肿瘤药物咨询委员会投票（2024年9月）反对在PD-L1联合阳性评分<1或TAP评分<1%的患者中使用程序性细胞死亡蛋白-1抑制剂进行一线治疗，因为其获益风险比不佳。因此，我们对RATIONALE-305研究中PD-L1 TAP评分≥1%的患者数据进行了回顾性分析。
方法
局部晚期不可切除或转移性HER2阴性GC/GEJC成年患者被随机分为每3周接受200 mg替雷利珠单抗或安慰剂联合ICC治疗。对PD-L1 TAP评分≥1%的患者，回顾性评估替雷利珠单抗联合ICC与安慰剂联合ICC的疗效和安全性结果。
结果
在最终分析截止日期（2023年2月28日），432例患者接受替雷利珠单抗联合ICC治疗，453例患者接受安慰剂联合ICC治疗，且PD-L1 TAP评分≥1%。与安慰剂联合ICC相比，替雷利珠单抗联合ICC观察到OS有具有临床意义的改善[分别为15.0个月（95%置信区间[CI] 13.3 - 16.7）和12.8个月（95% CI 12.1 - 14.1）；分层风险比0.77（95% CI 0.67 - 0.90）]。无进展生存期、总缓解率、缓解持续时间和疾病控制率也有所改善。在3年数据截止日期（2024年2月28日）时，OS的改善得以维持。替雷利珠单抗联合ICC具有可接受的安全性，无新的安全信号。
结论
对于局部晚期不可切除或转移性HER2阴性GC/GEJC且PD-L1 TAP评分≥1%的患者，替雷利珠单抗联合ICC是一种有效且可耐受的一线治疗方案。
试验注册号
NCT03777657。
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